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Document 11 Design of Antithrombotic Agents Directed at Factor Xa William C. Ripka Corvas International, Inc., San Diego, California I. Introduction Page 265 Serine proteases have long been recognized as important players in a number of biochemical processes and their specific and selective inhibition provides multiple therapeutic opportunities [1]. In particular, the blood coagulation process is the result of an amplified cascade of proteolytic events in which several specific zymogens of serine proteases in blood are activated sequentially by selective cleavages to produce active enzymes [2,3]. This process, in pathological circumstances, may lead to the formation of a thrombus—an insoluble matrix of fibrin and platelets. Thrombosis is a serious medical problem in the United States and Europe as exemplified by the fact that half the people who die each year die of cardiovascular related problems. While much recent work in antithrombotic therapeutic approaches has focused on inhibition of thrombin, the central role that Factor Xa plays in the coagulation response to vascular injury also makes it an ideal pharmacological target for antithrombotic drug development. The recent report of the x-ray crystal structure of native Factor Xa [4] allows, for the first time, a wellfounded structure-based drug design approach for inhibitors. A number of reviews describing the biology [5–10] and chemistry [11,12] of Factor Xa inhibitors have appeared. II. Coagulation Cascade In the coagulation cascade (Figure 1), a highly amplified process leads to the formation of thrombin, which is the primary mediator for the conversion of fibrinogen to fibrin, as well as activation of platelets through the thrombin http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_265.html [4/5/2004 5:11:42 PM]
Document Figure 1 The coagulation cascade. Page 266 receptor. Thrombin generation is itself, however, the result of Factor Xa in complex with Factor Va on a phospholipid surface (the prothrombinase complex) acting on prothrombin. Vascular injury is the initiating event in the coagulation process, causing the activation of Factor Xa by the Factor VIIa/tissue factor complex. Factor Xa is, therefore, a central and crucial enzyme directly leading to the production of thrombin and its inhibition should be effective in blocking thrombogenesis. As a consequence of its key role early in the coagulation cascade process Factor Xa represents a potentially valuable therapeutic target for potent and specific inhibition. III. Proof of Principle for a Factor Xa Inhibitor In recent years the method by which certain hematophageous organisms maintain blood flow during feeding has been determined. Interestly, several of these organisms utilize Factor Xa inhibitors to prevent coagulation [13–15]; the tick anticoagulant peptide (TAP), a small protein isolated from the Ornithidoros moubata tick [13], and antistasin isolated from the Haementeria officinalis leech [14] are both potent and selective inhibitors of Factor Xa. As expected, these molecules are effective antithrombotics in several animal models of thrombosis (Table 1) and provide an important proof of principle with regard to the potential effectiveness of Factor Xa inhibitors as therapeutic anticoagulants. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_266.html [4/5/2004 5:11:49 PM]
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Document D ddI, 152 tumour necrosis
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